The present invention generally relates to local therapies for the eye and, more particularly, to controlled-release ocular implant devices, including methods for making and using such devices, for delivery of therapeutic agents to the eye.
In the treatment of many diseases and disorders of the eye, and especially in the case of degenerative or persistent conditions, implantable sustained-release delivery devices have been desired that would continuously administer a therapeutic agent to the eye for a prolonged period of time.
Local ocular implants of a wide variety of constructions and placements have been proposed heretofore for dispensing a therapeutic drug to the eye.
For instance, U.S. Pat. No. 4,014,335 describes an ocular drug delivery device placed in the cul-de-sac between the sclera and lower eyelid for administering the drug and acting as a reservoir. The ocular device is characterized therein as administering drug to the eye in a controlled, continuous dosage rate over a prolonged time. To accomplish this, the ocular device comprises a three-layered laminate of polymeric materials holding the drug in a central reservoir region of the laminate. The drug diffuses from the reservoir through at least one of the polymeric layers of the laminate.
U.S. Pat. No. 5,773,021 describes bioadhesive ophthalmic inserts that are placed in the conjunctival sac, in which the inserts are prepared by extrusion, thermoforming, or heat compression of a polymeric material matrix and the drug to be delivered. The polymeric matrix comprises a water-soluble biocompatible polymer, such as hydroxyalkyl celluloses, maltodextrins, chitosans, modified starches or polyvinyl alcohols; a water-insoluble biocompatible polymer such as an alkyl cellulose; and where applicable a bioadhesive polymer such as polyvinyl carboxylic acid type polymers or certain bioadhesive polysaccharides or derivatives thereof. The ophthalmic inserts are characterized therein as intended for the prolonged and controlled release of a medicinal substance.
U.S. Pat. No. 5,773,019 describes a continuous release drug delivery implant which, among other mentioned places, can be mounted either on the outer surface of the eye or within the eye. A drug core is covered by a polymer coating layer that is permeable to the low solubility agent without being release rate limiting. Descriptions include a coating of cyclosporine A (CsA) drug cores with one or multiple coatings of polyvinyl alcohol solution, followed by heating to 110, 104 or 120xc2x0 C., presumably to cross link and harden the coating(s) in place around the core. Also described is a implant prepared by fixing a pellet directly over a smaller hole formed in a silicone film, followed by a suture being placed around the pellet in a gapped relationship thereto, and then the entire assembly is coated again with silicone to form the implant. The ocular device is characterized therein as giving a continuous release to an affected area, once implanted, and producing long-term sustained tissue and vitreous levels at relatively low concentrations.
U.S. Pat. No. 5,378,475 describes a sustained-release implant for insertion into the vitreous of the eye. The implant has a first impermeable coating, such as ethylene vinyl acetate, surrounding most, but not all, of a drug reservoir and a second permeable coating, such as a permeable crosslinked polyvinyl alcohol, disposed over the first coating including the region where the first coating does not cover the drug reservoir, to provide a location through which the drug can diffuse out of the implant. The implant also has a tab which can be used to suture the device in place in the eye. The implant devices are prepared by applying coating solutions, such as by dipping, spraying or brushing, of the various coating layers around the drug reservoir.
U.S. Pat. No. 5,725,493 describes an ocular implant device for providing drugs to the vitreous cavity over a period of time. The drug reservoir is attached to the outside of the eye with a passageway permitting medicament to enter the vitreous cavity of the eye. The above-listing of publications describing prior ocular implant systems is intended to be only illustrative in nature, and not exhaustive.
Local ocular implants avoid the shortcomings and complications that can arise from systemic therapies of eye disorders. For instance, oral therapies for the eye fail to provide sustained-release of the drug into the eye. Instead, oral therapies often only result in negligible actual absorption of the drug in the ocular tissues due to low bioavailability of the drug. Ocular drug levels following systemic administration of drugs is usually limited by the blood/ocular barriers (i.e., tight junctions between the endothelial cells of the capillaries) limit drugs entering the eye via systemic circulation. In addition, variable gastrointestinal drug absorption and/or liver metabolism of the medications can lead to dose to dose and inter-individual variations in vitreous drug levels. Moreover, adverse side effects have been associated with systemic administration of certain drugs to the eyes.
For instance, systemic treatments of the eye using the immune response modifier cyclosporine A (CsA) have the potential to cause nephrotoxicity or increase the risk of opportunistic infections, among other concerns. This is unfortunate since CsA is a recognized effective active agent for treatment of a wide variety of eye diseases and indications, such as endogenous or anterior uveitis, corneal transplantation, Behcet""s disease, vernal or ligneous keratoconjunctivitis, dry eye syndrome, and so forth. In addition, rejection of corneal allografts and stem cell grafts occurs in up to 90% of patients when associated with risk factors such as corneal neovascularization. CsA has been identified as a possibly useful drug for reducing the failure rate of such surgical procedures for those patients. Thus, other feasible delivery routes for such drugs that can avoid such drawbacks associated with systemic delivery are in demand.
Apart from implant therapies, other local administration routes for the eye have included topical delivery, such as ophthalmic drops and topical ointments containing the medicament. Tight junctions between corneal epithelial cells limit the intraocular penetration of eye drops and ointments. Topical delivery to the eye surface via solutions or ointments can in certain cases achieve limited, variable penetration of the anterior chamber of the eye. However, therapeutic levels of the drug are not achieved and sustained in the middle or back portions of the eye. This is a major drawback, as the back (posterior) chamber of the eye is a frequent site of inflammation or otherwise the site of action where, ideally, ocular drug therapy should be targeted for many indications.
Age-related macular degeneration (AMD) is a common disease associated with aging that gradually impairs sharp, central vision. There are two common forms of AMD: dry AMD and wet AMD. About ninety percent of the cases of AMD are the dry form, caused by aging and thinning of the tissues of the macula; a region in the center of the retina that allows people to see straight ahead and to make out fine details. Although only about ten percent of people with AMD have the wet form, it poses a much greater threat to vision. With the wet form of the disease, rapidly growing abnormal blood vessels known as choroidal neovascular membranes (CNVM) develop beneath the macula, leaking fluid and blood that destroy light sensing cells and causing a blinding scar tissue, with resultant severe loss of central vision. Wet AMD is the leading cause of legal blindness in the United States for people aged sixty-five or more with approximately 25,000 new cases diagnosed each year in the Unites States. Ideally, treatments of the indication would include inducing an inhibitory effect on the choroidal neovascularization (CNV) associated with AMD. However, in that the macula is located at the back of the eye, treatment of CNVM by topical delivery of pharmacological agents to the macula tissues is not possible. Laser photocoagulation, photodynamic therapy, and surgical removal is currently used to treat CNVM. Unfortunately, the recurrence rate using such methods exceeds 50% within a year of therapy.
As an approach for circumventing the barriers encountered by local topical delivery, local therapy route for the eye has involved direct intravitreal injection of a treatment drug through the sclera (i.e., the spherical, collagen-rich outer covering of the eye). However, the intravitreal injection delivery route tends to result in a short half life and rapid clearance, without sustained release capability being attained. Consequently, daily injections are frequently required to maintain therapeutic ocular drug levels, which is not practical for many patients.
Given these drawbacks, the use of implant devices placed in or adjacent to the eye tissues to deliver therapeutic drugs thereto should offer a great many advantages and opportunities over the rival therapy routes. Despite the variety of ocular implant devices which have been described and used in the past, the full potential of the therapy route has not been realized. Among other things, prior ocular implant devices deliver the drug to the eye tissues via a single mode of administration for a given treatment, such as via slow constant rate infusion at low dosage. However, in many different clinical situations, such as with CNVM in AMD, this mode of drug administration might be a sub-optimal ocular therapy regimen.
Another problem exists with previous ocular implants, from a construction standpoint, insofar as preparation techniques thereof have relied on covering the drug pellet or core with a permeable polymer by multi-wet coating and drying approaches. Such wet coating approaches can raise product quality control issues such as an increased risk of delamination of the thinly applied coatings during subsequent dippings, as well as thickness variability of the polymer around the drug pellets obtained during hardening. Additionally, increased production costs and time from higher rejection rates and labor and an increased potential for device contamination from additional handling are known problems with present implant technology.
Accordingly, this invention provides local treatment of a variety of eye diseases. The present invention also provides a method for the delivery of pharmaceuticals to the eye to effectively treat eye disease, while reducing or eliminating the systemic side effects of these drugs. This invention also provides sustained-release ocular implants for administration of therapeutic agents to the eye for prolonged periods of time. Additionally, this invention provides multi-modal sustained-release ocular implants. The invention also provides methods for making ocular implants with reduced product variability. The invention also provides methods for making ocular implants well-suited for ocular treatment trials using animal models. Other advantages and benefits of the present invention will be apparent from consideration of the present specification.
The present invention provides ocular implant devices for the delivery of a therapeutic agent to an eye in a controlled manner. The invention also includes fabrication and implementation techniques associated with the unique ocular implant devices that are presented herein.
In one embodiment of this invention, ocular implants are provided which administer a therapeutic drug to the eye according to dual mode release kinetics during a single treatment regimen. For instance, an ocular implant under this embodiment of this invention delivers drug continuously to the eye by initial delivery at a high release rate to eye tissues soon after placement of the implant in or near the eye, as a first administration mode, followed by drug delivery via a continuous, sustained lower release rate thereafter, as a second administration mode, and within the same treatment regimen using the same implant device. The delivery of drug is never interrupted during the regimen, as a smooth transition occurs in the changeover from the high to low release rate modes of drug delivery during the regimen. In this manner, the delivery of drug by the implant is dual mode or dual action in nature. Animal model studies have been performed, which are described elsewhere herein, that confirm this dual mode performance capability in local eye therapies for several embodiments of implants of this invention. As a consequence, no intervention is needed between initiation of the treatment, i.e., installing the ocular implant, and discontinuation of the treatment regimen, i.e., exhaustion of the drug reservoir after a prolonged period of time.
Although not desiring to be bound to any particular theory, a large initial dosage is delivered at a relatively high release rate to the eye tissues via an ocular implant according to one embodiment of the present invention in a manner effective to substantially saturate the eye compartments, permitting an ensuing lower release rate, maintenance dosage delivered over a period of time by the same implant to more effectively reach the target site of treatment, even if located in a posterior chamber of the eye. A dual mode implant according to the embodiment of this invention provides the sustained-release of the therapeutic agent for a prolonged period of time after the period of high release kinetics.
For purposes of this application, the term xe2x80x98loading dosexe2x80x99 refers to a rapid release phase of a pharmacological drug in a mammalian organism in which an initial high release rate of the drug is observed followed by exponential or nearly exponential decline or decay in the release rate as a function of time. The terminology xe2x80x98sustained dosexe2x80x99 refers to the phase during which release rates are substantially constant over a prolonged period of time, and consequently concentration of the therapeutic agent in the eye tissues achieves a substantially steady state value over that period of time. The terms xe2x80x98loading dosexe2x80x99 and xe2x80x98sustained dosexe2x80x99 are used in connection with drug treatments of the eye, unless indicated otherwise. Moreover, from a pharmacological standpoint, the initial dosage delivered at a relatively high release rate constitutes a loading dose, and the sustained lower release rate dose constitutes a maintenance dosage, suitable for the effective treatment of an eye disease, disorder, ailment or condition. The terms xe2x80x9cdosexe2x80x9d and xe2x80x9cdosagexe2x80x9d are used interchangeably herein.
The present invention embodies implants which can provide such dual mode (xe2x80x9cdual actionxe2x80x9d) performance, or optionally other modes of therapy via modified configurations thereof which are also described herein.
One aspect of the invention relates to xe2x80x9cmatrixxe2x80x9d type implants, so referenced occasionally herein for convenience sake as every embodiment of implant under this category at least includes a composite matrix of polymer and therapeutic agent dispersed therein.
In one embodiment of this aspect of the invention, an implant provides therapeutic agent to the eye, in which the implant includes:
(a) a composite material matrix layer including:
(i) a therapeutic agent, and
(ii) a polymeric matrix material into which the therapeutic agent is dispersed, including (1) a polymer permeable to the therapeutic agent and present as a bioerodible solid matrix structure, and (2) a water-soluble polymer having greater water solubility than the permeable polymer, and
(b) optionally, a discrete solid core containing additional therapeutic agent, which is surrounded and covered by the composite material matrix layer.
This matrix type implant configuration is particularly well-suited for subconjunctival or intravitreal placement, but is not limited thereto and could be installed on or in other eye regions where convenient and useful.
In a more specific embodiment, the composite material matrix layer component of the matrix type implant comprises about 5 to about 50 wt % permeable polymer, about 0.05 to about 90 wt % water-soluble polymer, and about 1 to about 50 wt % therapeutic agent. Preferably, the composite material matrix layer component comprises about 5 to about 20 wt % permeable polymer, about 0.05 to about 20 wt % water-soluble polymer, and about 1 to about 50 wt % therapeutic agent. As fabricated, the implant is a solid structure.
In one preferred embodiment of the matrix type implant, the permeable polymer is a superhydrolyzed polyvinyl alcohol (PVA), which permits diffusion of the therapeutic agent therethrough, and forms a slowly bioerodible solid structure, and the water-soluble polymer is a pharmaceutical grade cellulose ether. Uncrosslinked superhydrolyzed PVA releases the drug by surface erosion of the PVA and by diffusion of the drug through the superhydrolyzed PVA. The rate of erosion of the superhydrolyzed PVA is sufficiently slow that the polymer material in the implant will dissolve so that the therapeutic agent pellet (xe2x80x9cdrug pelletxe2x80x9d), when included, will disintegrate only after an extended period of time, such as months or even years, in order to provide a slow sustained delivery of drug.
In addition, the superhydrolyzed PVA is water permeable and permeable to the therapeutic agent in a predictable manner upon saturation with body fluids, yet offers the advantage of undergoing very limited expansion when the implant is installed. The low wet expansion behavior of superhydrolyzed PVA prevents the implant from being extruded, and also permits more predictable pharmacokinetic behavior of the device. Also, the superhydrolyzed polyvinyl alcohol used in the polymeric matrix material is essentially noncrosslinked through its secondary hydroxyl functionality, i.e., it is not heated to temperatures during preparation of the implant sufficient to induce a level of crosslinking which impairs its permeability to the therapeutic agent present in either the inner core or the composite material matrix layer. The superhydrolyzed PVA is slowly bioerodible and not rapidly water-soluble in body fluids, so that the inner core does not disintegrate soon after installation of the implant. For purposes of this invention, a superhydrolyzed polyvinyl alcohol is a polyvinyl alcohol having at least 98.8 wt % hydrolysis, preferably at least 99.0 wt % hydrolysis, and most preferably at least 99.3 wt % or more hydrolysis. Generally, the superhydrolyzed polyvinyl alcohol for use in this invention generally have a weight average molecular weight of about 85,000 to about 150,000, and preferably about 100,000 to about 145,000.
On the other hand, the separate water-soluble polymer included in the polymeric matrix material provided in the matrix type implant preferably is a nonionic cellulose ether polymer. The cellulose ether polymer used generally has a weight average molecule weight of about 70,000 to about 100,000, and preferably about 80,000 to about 90,000. The water-soluble polymer is used as a processing aid during preparation of the composite material matrix layer. Namely, it acts as a suspension and dispersion aid for introducing the therapeutic agent into an aqueous medium, and before admixture with the superhydrolyzed PVA ingredient, in a premix step involved with fabricating the implant (discussed in more detail below). Examples of such cellulose ether compounds include hydroxyalkyl cellulose materials, such as hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), and hydroxyethyl cellulose (HEC). In general, the higher the proportion of cellulose ether present in the polymeric matrix part of the matrix implant relative to the proportion of superhydrolyzed PVA, the more rapid the release of the therapeutic agent.
In one preferred embodiment of the matrix implant, a therapeutic agent is included in both the inner core or pellet and the exterior composite material matrix layer or cladding. This results in a dual mode release of the therapeutic agent or drug into the eye during a treatment regimen. That is, a loading dose is initially delivered to the eye by the matrix implant followed by a transition in the release rate, continuing uninterrupted drug delivery by the implant, down to a relatively steady maintenance dosage that is sustained over a prolonged period. Initially, the therapeutic agent is released both from the polymer matrix and the inner core or pellet of this embodiment of implant, creating the rapid release rate of the loading dose. Once the concentration of drug initially preloaded into the composite drug/polymer matrix cladding material diffuses into the eye, the maintenance dosage of drug is derived at a relatively constant rate from the remainder of the drug diffusing from the inner core or pellet through the composite material matrix layer which surrounds the core.
Moreover, an added advantage of this embodiment is that this dual mode therapy can be achieved via subconjunctival implant placement for some eye treatments. Thus, a less invasive and simpler procedure that does not require piercing of the vitreous body is provided. Used as a subconjunctival implant, it can be placed behind the surface epithelium within the subconjunctival space. It also is possible to install these implants at or near other specific sites on or within the eye, such as intravitreal, if desired or useful.
This matrix implant embodiment of the invention also can be deployed for single mode or single action therapy in the eye by omitting the solid core or pellet of therapeutic agent, and using the composite material matrix layer alone, which is the same general construction as that used in the dual mode device. The single mode matrix implant releases a loading dose for a short period of time (e.g., up to about 30 days), but does not provide a sustained maintenance dosage over a prolonged period thereafter.
In an optional configuration, a portion of the outer surfaces of the matrix implant, such as one side of the composite material matrix layer, has a top coat provided that is a polymeric material that is impermeable to the therapeutic agent, such as polymethyl methacrylate (PMMA). In this way, the release rate of the matrix implant can be reduced in a managed manner, if desired.
As another alternative embodiment of matrix implant according to this invention, poly(ethylene vinyl) acetate (EVA) control can be used in the polymeric matrix material in lieu of the superhydrolyzed PVA. EVA is nonbiodegradable and permeable to water. In the same general manner as the PVA-based matrix implants, the EVA-based matrix implants can provide dual mode or single mode drug release depending on whether the drug pellet is included (dual mode, i.e., loading plus slow constant rate release) or not (single mode, i.e. slow constant rate release only).
Both the dual mode and single mode variants of the matrix implants of this invention are well-tolerated and non-toxic to the patient or recipient (i.e., a mammalian hostxe2x80x94human or veterinary). In addition, the matrix implant design of this invention can be prepared by unique methodologies and selections of materials leading to and imparting the unique pharmacological performance properties present in the finished devices.
Among other eye therapies, the matrix implant of the present invention, such as when used in a subconjunctival placement, provides an effective treatment in corneal transplantation procedures to reduce rejection rates. For example, an immune system modifier agent such as cyclosporine can be delivered non-systemically to the eye, in order to reduce rejection rates of corneal allografts. Alternatively, this implant can be installed in the vitreous humor to deliver 2-methoxyestradiol (occasionally abbreviated herein as xe2x80x9c2ME2xe2x80x9d) for treatment of CNVM. Also, other drugs or drug cocktails can be delivered as desired and appropriate.
Another aspect of the invention relates to xe2x80x9creservoirxe2x80x9d type implants which include a silicone-encapsulated reservoir containing therapeutic agent. The reservoir type implants of this invention are intraocular, and preferably intravitreous implants. The intraocular reservoir implants are sustained-release devices which deliver therapeutic agent to the eye over a prolonged period of time.
The intraocular reservoir implant generally includes an inner core comprising a therapeutic agent for the eye covered by, and radially centered within, a polymeric layer comprising a nondegradable material permeable to the therapeutic agent, as a subassembly, and an ocular attachment means affixed to an exterior surface of the polymeric layer of the subassembly. In a preferred embodiment of the invention, the nondegradable material is silicone.
Methodologies are used in this intraocular reservoir implant configuration which ensure that the silicone is degassed and that the inner core is well-centered, at least radially, within a polymer comprising silicone. This results in unhindered diffusion of the drug from the reservoir through the silicone, as air bubbles or pockets are eliminated which otherwise would not permit such diffusion. As a result, a controlled and predictable drug release rate can be obtained. Centrifugation is used in conjunction with a temporary thin walled tubular mold made of low adhesion plastic in a multi-step process effective to degas the silicone encapsulating material and radially center the drug core within a polymeric material before the polymeric material is fully hardened.
In one embodiment of preparing the intraocular reservoir implant, the steps of the method generally include positioning a thin walled tube made of low adhesion (releasable) plastic, such as a polytetrafluoroethylene tube, in a temporarily fixed upright position within a centrifuge tube. A base made of hardened silicone, or a polymeric material having similar permeability, is then formed at the bottom section of the plastic tube, such as by introducing a curable silicone fluid in the bottom of the microcentrifuge tube, positioning a bottom section of plastic tube below the surface of the curable silicone fluid. This is done in a manner such that the silicone fluid infiltrates and fills a lower section of the plastic tube, and also fills the space between the outer surface of the lower section of the plastic tube and the inner facing wall of the centrifuge tube, followed by curing or hardening the silicone fluid to hold the plastic tube in an upright position within the microcentrifuge tube. Thereafter, a drug pellet, as the drug core, is introduced into the plastic tube followed by addition of additional wet silicone into the plastic tube. The microcentrifuge tube is centrifuged as needed to degas the additional silicone and place, if necessary, the pellet on the silicone base positioned at the bottom of the plastic tubing. The additional curable silicone fluid added inside the plastic tube is sufficient to completely immerse the exposed surfaces of the pellet as it rests on the hardened silicone base. As needed, the drug pellet can be manually or mechanically centered on the silicone base using an insertable/retractable device or probe to move and center the pellet as needed. The added silicone fluid is then cured inside the plastic tube. After the silicone is cured, the plastic tube is separated from the centrifuge tube, and the resulting silicone-coated pellet reservoir type implant is in turn removed from the releasable plastic tube, as an implant subassembly. The reservoir implant subassembly is joined to a means for attaching the implant subassembly to intraocular tissues of the eye, such as a suture stub.
As an alternative to the suture stub, a silk mesh fabric can be embedded in the silicone at one end of the reservoir type implant. This allows a suture to pass through the mesh embedded at the one end and the suture will not scissor through the soft silicone since it is caught by the mesh. The suture then passes through the edges of the scleral wound and is tied down.
The implant subassembly of the intraocular reservoir implants of the invention provide a sustained, substantially constant delivery rate of drug over a prolonged period. The intraocular reservoir implants also can be modified to form dual mode release devices. For instance, in a dual mode configuration, additional therapeutic agent could be dispersed in the silicone fluid before being used to encapsulate the drug core to create an initial higher release rate, or loading dose; alternatively, additional amounts of the drug could be dispersed in or attached as a discrete inlay member onto a separate silicone adhesive used to attach a surface of the reservoir implant subassembly to a suture stub or the like. Alternatively, multi-drug therapy could be provided by including a drug different from the drug core in the silicone surrounding the pellet or, in or on the silicone adhesive used to affix the implant reservoir subassembly to the suture stub. In another embodiment, more than one reservoir implant subassembly, each comprising an encapsulated drug core, can be attached to a common suture stub to provide concurrent delivery of different drugs or additive introduction of a common drug.
As another dual mode embodiment of the reservoir implant, a circular wafer shaped pellet or tablet of therapeutic agent having a larger radial diameter than thickness can be fixed to a suture stub with silicone adhesive; and a temperature-curable type silicone adhesive is then used to form a coating bead around the periphery of the wafer-shaped pellet or tablet. Curing the bead of silicone coating around the tablet periphery can be delayed (preferably for about 18 to 30 hours, more preferably approximately 24 hours), by keeping the coated assembly at room temperature (e.g., 20-30xc2x0 C.); thereafter peripheral bead coating of silicone ultimately becomes fully cured. The silicone adhesive is in a constant state of curing but the process is not complete for 18-30 hours. The top surface of the tablet is coated separately with silicone before or after this xe2x80x9cdelay in curexe2x80x9d procedure, and cured. During the interim delay in cure period, some, but not all, of the therapeutic agent diffuses into the surrounding nonfully cured silicone coating polymer at its periphery, which creates a high release rate or loading dose when the implant is initially installed, followed by slow, lower dosage sustained release of the therapeutic agent.
Among other eye therapies, the intraocular reservoir implants of the present invention provide an effective treatment for sight-threatening eye diseases that include but are not limited to uveitis, age-related macular degeneration, and glaucoma. Therapeutic agents useful in this implant design include, for example, 2-methoxyestradiol (2ME2) or angiogenesis compounds such as VEGF antagonists for treating CNVM; or corticosteroids for treating uveitis, to name just a few examples.
The therapeutic agents and drugs deliverable by the implants of this invention generally are low solubility substances relative to the various polymeric matrices described herein, such that the agents diffuse from the drug core into and through the polymer material, when saturated with body fluids, in a continuous, controlled manner.
The therapeutic agents and drugs that can be delivered by the implants of this invention include, for example, antibiotic agents, antibacterial agents, antiviral agents, anti-glaucoma agents, antiallergenic agents, anti-inflammatory agents, anti-angiogenesis compounds, antiproliferative agents, immune system modifying agents, anti-cancer agents, antisense agents, antimycotic agents, miotic agents, anticholinesterase agents, mydriatic agents, differentiation modulator agents, sympathomimetic agents, anaesthetic agents, vasoconstrictive agents, vasodilatory agents, decongestants, cell transport/mobility impending agents, polypeptides and protein agents, polycations, polyanions, steroidal agents, carbonic anhydride inhibitor agents, and lubricating agents, and the like singly or in combinations thereof.
In these and other ways described below, the inventive implants offer a myriad of advantages, improvements, benefits, and therapeutic opportunities. The inventive implants are highly versatile and can be tailored to enhance the delivery regimen both in terms of administration mode(s) and type(s) of drugs delivered. The implants of this invention permit continuous release of therapeutic agents into the eye over a specified period of time, which can be weeks, months, or even years as desired. As another advantage, the inventive implant systems of this invention require intervention only for initiation and termination of the therapy (i.e., removal of the implant). Patient compliance issues during a regimen are eliminated. The time-dependent delivery of one or more drugs to the eye by this invention makes it possible to maximize the pharmacological and physiological effects of the eye treatment. The inventive implants have human and veterinary applicability.